Atypical mycobacteria or nontuberculous mycobacteria are organisms that cause a variety of diseases such as skin and soft tissue infection, lymphadenitis, pulmonary infection, disseminated infection, and a wide range of more rarely encountered infections. The most commonly encountered atypical mycobacteria that cause the majority of infection in humans are the Mycobacterium avium complex bacteria (MAC), Mycobacterium avium and Mycobacterium intracellulare, also referred to as Mycobacterium avium-intracellulare (MAI), Mycobacterium kansasii, Mycobacterium marinum, Mycobacterium ulcerans, Mycobacterium abscessus complex bacteria (abscessus, massiliense, and bolletii), Mycobacterium chelonae, and Mycobacterium fortuitum. These organisms are most commonly found in the soil, indoor and outdoor water sources, and are recognized to colonize poorly sanitized medical equipment. Atypical mycobacteria most commonly infect young children, immunocompromised individuals, individuals with indwelling medical equipment, and those who have recently undergone surgical or non-surgical procedures. These bacteria can be further categorized into slow and rapidly growing organisms and grouped by the organ systems which they most commonly affect. Due to their morphology and growth patterns, atypical mycobacteria are difficult to identify on diagnostic testing. Treatment often requires extended courses of combination antibiotic therapy frequently with surgical intervention.
One defining feature of most atypical mycobacteria is that they are acid-fast bacilli. This staining property detected via the Kinyoun method is due to its hydrophobic mycolic acid outer layer. It is this mycolic acid layer that allows them to form thick biofilms, enabling their survival in harsh environments that are not as well tolerated by other bacteria. These biofilms stunt the ability of antibiotics to penetrate bacteria effectively. They allow for survival in varying temperatures and protect the bacteria from being killed by water purifying chemicals such as chlorine, disinfectants, and cleaning products. Biofilms also allow the bacteria to survive in oxygen-rich and anaerobic environments. Another defining characteristic of mycobacteria is their slow rate of growth. Atypical mycobacteria are divided into rapid and slow-growing categories. The rapid-growing organisms take 7 to 30 days to grow on culture. The slow-growing organisms will take several weeks to months to demonstrate growth. The type of disease caused by these organisms is dependent on the mode of inoculation and the susceptibility of the host to infection. Pulmonary infection occurs via inhalation of aerosolized material containing the bacteria, whereas lymphadenitis is often caused by ingestion or penetration through the soft tissues, and skin and soft tissue infection by access though skin breakdown or by indwelling medical equipment.
Atypical mycobacteria are found in both natural and human-made environments. In nature, they are found in the highest concentrations in the soil and water. Geographically they have higher concentrations in pine forests and the swamp-like regions of the southern United States. They also inhabit plumbing and human-made water sources with higher concentrations in urban areas. They are resistant to water treatment chemicals and can be found in drinking water, showers, hot tubs, and saunas. Estimates of the rate of pulmonary disease are between 5 to 10 per 100,000 per year. Various studies have estimated the rate of all causes of atypical mycobacterial infection in children to be between 0.6 to 3.3 per 100,000. Estimates of the rate of all causes of infection in adults are between 20 to 47 per 100,000.
MAC/MAI pulmonary disease is most commonly found in adults and those with impaired host defense of the lung, such as Human immunodeficiency virus (HIV), patients on TNF-alpha inhibitors, and cystic fibrosis. Adult pulmonary disease preferentially impacts White, middle-aged, or older men, who often have comorbid diagnoses of chronic obstructive pulmonary disease, alcohol use, or tobacco use. A less common presentation referred to as "hot tub lung" can be seen as part of a hypersensitivity syndrome following MAC exposure related to bathing or recreational water exposure. Disseminated MAC/MAI is primarily observed in patients with significantly immunocompromised states such as acquired immunodeficiency syndrome (AIDS).
When encountered by the immune system, atypical mycobacteria are taken up by macrophages, causing the macrophages to release IL-12 and TNF-alpha. IL-12 release activates the IL-12-interferon gamma pathway. This pathway further recruits additional macrophages, neutrophils, and T-cells. This process ultimately results in the killing of these intracellular bacteria by nitric oxide and free radicals. The macrophages, neutrophils, and T-cells recruited to the site of infection can sometimes result in granuloma formation, creating a fibrinous mass walling off the infection and isolating it from the rest of the body. Atypical mycobacteria are often able to evade this response due to the ability of the glycoproteins in their cell wall to inactivate the phagosome-lysosome fusion process, and free radical destruction allowing the bacteria to live as intracellular organisms within macrophages.
Lymphadenitis: According to the American Thoracic Society and Infectious Disease Society of America, Mycobacterium avium complex bacteria cause approximately 80% of atypical mycobacterial infections in children. The progression of atypical mycobacterial lymphadenitis has been described in four stages by Toretta et al. (2018). The first stage describes a unilateral submandibular, preauricular, or cervical chain lymph node that slowly and painlessly enlarges over several days to months. Stage one was noted by the author to be unlikely to show systemic symptoms. Stage two describes the presence of tenderness indicative of necrosis within the lymph node. Stage three describes erythematous discoloration of the overlying skin. Stage four describes the progression of skin breakdown to the formation of sinus tracts.
Pulmonary: The three species that make up the vast majority of atypical mycobacterial pulmonary infections are the Mycobacterium avium complex bacteria (approximately 80%), Mycobacterium kansasii, and Mycobacterium abscessus. Mycobacterium avium complex infections can be further grouped into two different presentations. The first presentation is found more commonly in middle-aged males with the risk factors of long term alcohol and tobacco abuse. In these patients, the MAC bacteria tend to form large fibrocavitary lesions in the apex of the lung. These lesions can rapidly progress to encompass significant areas of the lung within 1 to 2 years and generally result in morbidity and mortality at a much faster rate. The second type of presentation of MAC lung disease more commonly affects postmenopausal caucasian women. In this presentation, the bacteria form small pulmonary nodules and cylindrical bronchiectasis with a concentration of nodules in the right middle lobe and ligula of the left upper lobe of the lungs. Similar presentations to MAC pulmonary disease are seen with Mycobacterium kansasii and abscessus. Mycobacterium kansasii tends to form large fibrocavities in the apex of the lung, similar to the first type of MAC disease presentation. A much smaller proportion of infections resemble the nodular and bronchiectatic type of presentation. Mycobacterium abscessus infection presents the majority of the time with a nodular and bronchiectatic presentation concentrated in the upper lung fields. Mycobacterium abscessus will form fibrocavities in approximately 15 percent of infections.
Skin and Soft Tissue: Atypical Mycobacteria enter the skin and soft tissue through trauma, surgical procedures, or via indwelling medical equipment. All species of atypical mycobacteria can cause skin and soft tissue infection. The most common species to cause skin and soft tissue infection are Mycobacterium chelonae, abscessus, fortuitum, ulcerans, and marinum. Mycobacterium marinum infection is also known as the fish tank granuloma, after originally being discovered to cause soft tissue infection in fish tank workers/enthusiasts. It most commonly causes localized erythema and granuloma formation of the digits, which can progress to nodular lymphangitis of the hands and forearms similar in appearance to sporotrichosis. These bacteria more rarely can affect tendons, joint spaces, and cause osteomyelitis. Immunocompromised patients have had recorded cases of disseminated infection. Mycobacterium ulcerans is also known as the Buruli ulcer. These ulcers are known for their large areas of skin involvement, deep ulceration, and marked cosmetic disfigurement. They most commonly begin as a small, painless nodule, which slowly begins to ulcerate. These ulcers are characterized by poorly defined and irregular borders and can cover very large sections of the body. Other variations of these lesions may also begin as localized erythema, subcutaneous edema, or a violaceous skin rash. Of note, approximately 15% of Mycobacterium ulcerans infections cause osteomyelitis. Mycobacterium fortuitum most commonly presents as a solitary subcutaneous nodule. The majority of cases of Mycobacterium fortuitum infection have low morbidity and limited infection. Immunocompromised patients, however, have been known to suffer from the more serious and disseminated infection. Mycobacterium abscessus most commonly forms an abscess under the site of skin trauma/penetration. These abscesses are painful to the touch, may form draining sinus tracts, and may progress to ascending lymphadenitis. Disseminated disease can occur in immunocompromised individuals and produce diffuse subcutaneous nodules with lymphadenitis. Mycobacterium chelonae presents in the majority of cases as small disseminated cutaneous nodules that are painful to the touch. The skin surrounding these lesions is often hyperpigmented. Lesions may also drain, form sinus tracts, appear as cellulitis, or non-healing ulcers. Infection is most common in immunocompromised patients. Mycobacterium chelonae has also been known to cause osteomyelitis.
Atypical mycobacteria contain a hydrophobic mycolic acid layer in their cell wall. Due to this property, they are not typically seen using Gram staining. The best method for the detection of atypical mycobacteria is fluorochrome staining, a type of acid-fast staining where these bacteria will appear as yellow to orange bacilli. Of note, rapidly growing mycobacteria are frequently not seen even with fluorochrome staining, and atypical mycobacteria overall are visualized in only 30% to 60% of cases. Rapidly growing mycobacteria are noted to be more sensitive to the decolorization process in acid-fast staining, and it is thought that using more delicate methods for decolorization can increase the chance of visualizing these bacteria. Other less sensitive methods of staining that may also be used include the Ziehl-Neelsen method and the Kinyoun stain.
The majority of the cases of mycobacterial lymphadenitis will present in children under the age of five whose parents have noticed one or more soft but firm, unilateral, subcutaneous masses usually in the submandibular or cervical chain regions. The masses are usually non-tender at the beginning of the disease, followed by the later development of fluctuance, and even purulent discharge from fistulizing tracts. Frequently a diagnosis of mycobacterial lymphadenitis is suspected after enlarged cervical nodes in children fail to respond to empiric antibiotic therapy directed at Staphylococcus and Streptococcus or fail to resolve under watchful-waiting for a presumed viral process.
Skin and Soft Tissue Infections
Mycobacterial skin and soft tissue infections can be the result of localized or disseminated infection, and occur in patients of all ages. Patients with localized lesions may give a history in which they experienced trauma to their skin while swimming (freshwater, saltwater, swimming pool, hot tubs). Other risk factors for skin and soft tissue infections include patients who are currently immunosuppressed or have had recent surgical procedures. Skin lesions can range from erythematous papules/nodules that progressively ulcerate, to ecthyma, resembling cellulitis. A separate category of skin lesion, the Buruli ulcer, is characteristic of a painless area of soft tissue swelling that slowly begins to ulcerate with poorly defined and irregular borders. Untreated, they can grow from a few centimeters to span large areas of the body. Patients with these lesions are usually from West Africa, Central, and South America, Australia, and Japan.
Mycobacterial pulmonary infection typically presents in patients with impaired host defense of the lung. This includes patients with cystic fibrosis, chronic obstructive pulmonary disease, HIV, and other immunodeficiency syndromes. In patients without known immunodeficiency syndromes, patients are more often male, middle-aged or older, and have a history of comorbid alcohol and/or tobacco abuse. These patients present in all cases with cough and worsening respiratory function, but can also present with pneumonia, hemoptysis, persistent fever, and weight loss. These patients tend to have a much more rapidly progressing disease. Another subset of patients with a more slowly progressing disease and similar symptoms has been identified as women who have undergone menopause, have a lower BMI, scoliosis, or rib cage abnormalities.
Mycobacteria can be difficult to detect by laboratory testing. The initial workup for most infections begins with a CBC, which can show a normal to elevated white blood cell count. Inflammatory markers such as C-reactive protein and erythrocyte sedimentation rate can also be normal or elevated. Samples from fluid cultures obtained from soft tissue lesions or excised lymph nodes should undergo acid-fast or fluorochrome staining. Organisms are visualized in around 30% to 60% of cases. Culture of fluid and tissue samples should be obtained and yields an organism in approximately 65% of cases. 90% of patients diagnosed with a disseminated infection will have positive blood cultures. Unlike the growth of common bacteria on culture, rapidly growing mycobacteria will take approximately 1 week or more to grow, and slow-growing mycobacteria will take several weeks to months to show growth. Polymerase chain reaction (PCR) is frequently used on samples to obtain faster results and is more sensitive in diagnosis, yielding an organism around 91% of the time. Tuberculin skin testing can also be used as a nonspecific method to confirm suspected atypical mycobacterial infection. It will result in a greater than 10 mm area of induration between 30% to 60% of the time. Diagnosis of pulmonary infection is currently based on clinical suspicion of an active infection given active pulmonary symptoms, findings on chest X-ray or CT, and growth on 2 or more sputum cultures (also accepted is tissue biopsy or lavage cultures).
Recommended treatment for adults and children with MAC infections includes azithromycin, rifampin, and ethambutol. Additional drug options are available for each drug class. Three times per week dosing is used in adult nodular/bronchiectatic disease with recommended regimens of azithromycin 500 to 600 mg or clarithromycin 1000 mg, plus ethambutol 25 mg/kg, plus rifampin 600 mg. Daily dosing is required in cavitary disease with the additional option of three times weekly streptomycin or amikacin. Recommended daily dosages are: clarithromycin 500 to 1000 mg or azithromycin 250 to 300 mg, plus rifampin 450 to 600 mg, with either amikacin or streptomycin. The American Thoracic Society and Infectious Disease Society of America cite a study that suggests tolerated dosages of 25 mg/kg three times weekly for both drugs. They also state that certain experts recommend considering decreasing dosages to 8 to 10 mg/kg (maximum 500 mg) for patients older than 50 years or those who are receiving treatment longer than 6 months. Antibiotics are continued until the patient has had 12 months of negative sputum cultures. Typical time to the first negative sputum culture is 3 to 6 months, with the majority of patients obtaining negative sputum cultures within 12 months. Treatment failure is defined as the lack of sputum conversion after 12 months or the lack of sputum conversion within 6 months without any improvement clinically or on imaging. In cases of progressively worsening respiratory status where patients continue to fail sputum conversion, surgical resection of the lung parenchyma containing the cavitary disease may be required.
Mycobacterium intracellulare has demonstrated rising minimum inhibitory concentrations and overall increased resistance to anti-mycobacterial agents in comparison to Mycobacterium avium, making it more complicated to treat at times.
Alternative agents utilized to treat MAC/MAI pulmonary disease includes inhaled amikacin, clofazimine (as a substitute for rifampin), and moxifloxacin.
Several other atypical mycobacterial species have been shown to cause pulmonary disease and are generally susceptible to macrolides, rifampin/rifabutin, streptomycin, amikacin, doxycycline, and fluoroquinolones. Of note, the pulmonary disease caused by Mycobacterium abscessus is resistant to most antibiotics and can only be cured in a minority of patients by surgical resection. Those that are not cured are administered chronic intermittent antibiotic therapy to attempt to slow disease progression.
Treatment for lymphadenitis is based on a two-drug regimen of one macrolide, azithromycin, or clarithromycin, in combination with rifampin or ethambutol. Antibiotics are dosed daily and taken until the resolution of symptoms. Surgical resection of infected lymph nodes and tissue is typically used in combination with antibiotic therapy with significantly increased cure rates. The initial antibiotic regimen may be adjusted based on culture susceptibility results.
Skin and Soft Tissue
Skin and soft tissue infections are treated with combination antibiotic therapy with a variety of options available, including macrolides, doxycycline, fluoroquinolones, trimethoprim/sulfamethoxazole, cephalosporins, or linezolid. Empiric therapies are adjusted once susceptibility testing yields results; however, combination antibiotic therapy is continued due to inducible antibiotic resistance. Surgical debridement is required for infections that are extensive and associated with necrosis.
Pulmonary: Treatment of Mycobacterium avium lung disease is successful in approximately 39% of patients with a 12% 5-year mortality rate. High levels of morbidity and mortality are seen in strains that exhibit macrolide resistance with a significantly higher 47% mortality rate at 5 years. Outcomes of pulmonary Mycobacterium abscessus infection are poor, with only around 41% of patients achieving sputum conversion with surgical and antibiotic intervention. Approximately 34% of patients achieve sputum conversion with antibiotics alone.
Lymphadenitis: Children with lymphadenitis caused by Mycobacterium avium are cured in 95% of cases where both surgical excision and antibiotic therapy are used.
Skin and Soft Tissue Infection: Resolution of infection is achieved in the vast majority of patients with Mycobacterium marinum, abscessus, ulcerans, fortuitum, and other skin and soft tissue infections when proper antibiotic and surgical treatments are utilized.
Mycobacterial lymphadenitis can result in fistula formation and repeated need for surgical intervention. Excision of preauricular nodes risks paralysis of the facial nerve as it courses through the underlying parotid gland. Repeated surgical procedures and scarring from the skin and soft tissue infection can result in cosmetic disfiguration. Since most cases of lymphadenitis occur in the neck and facial region lymph nodes in young children, careful consideration of the psychosocial consequences of cosmetic disfiguration from repeated surgical procedures must be weighed against the chances of improved outcomes. The curative rate with antibiotics alone ranges from approximately 66% to 73%, which increases to around 95% with surgical intervention.
The ability of patients with advanced age and multiple comorbidities to tolerate the prolonged combination of antibiotic therapy or possible surgical intervention required to treat pulmonary disease necessitates the discussion of chronic suppressive therapy vs. curative therapy. Clarithromycin can cause gastrointestinal upset and may need to be divided into twice-daily dosing. Azithromycin can prolong the QT interval and might have to be avoided due to other medications previously prescribed to patients. Rifabutin can cause leukopenia and uveitis. Ethambutol can cause optic neuritis, and patients should be screened for decreases in visual acuity and color blindness. Severe pulmonary infection resulting in lobectomy can result in chronic respiratory complications even when the intervention is curative.
Skin and soft tissue infections associated with medical complications can be prevented by only seeking the services of licensed medical providers. Special patient populations such as those with cystic fibrosis, HIV, or other immunocompromised patients should follow their subspecialist's recommended treatment guidelines for the prevention of opportunistic infection.
If infection with atypical mycobacteria is suspected, an infectious disease specialist should be consulted to help guide diagnostic testing and treatment management. Coordination with surgical specialists is necessary for many presentations of mycobacterial disease. Diligent office managers and nursing staff are vital to treatment outcomes due to the need for frequent follow-up appointments and long term treatment in select patients.
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